1. Field of the Invention
This invention relates to novel polyprenyl compounds and methods of producing the same. More particularly, it relates to novel polyprenyl compounds which are useful as intermediates for the synthesis of mammalian dolichols and methods of producing the same.
2. Description of the Prior Art
Dolichol was first isolated in 1960 from human kidney and animal tissues such as ox kidney, pig kidney, pig heart, pig liver and rat liver by J. F. Pennock et al. [see Nature (London), 186, 470(1960)]. Later, it was revealed that dolichol is a mixture of polyprenol homologs having the general formula ##STR3## wherein ##STR4## represent a trans-isoprene unit and a cis-isoprene unit, respectively (the same definition shall apply throughout the present specification), and the number j of cis-isoprene units in the above formula is generally distributed between 12 to 18 and three homologs in which j is 14, 15 and 16 are present in major proportions [R. W. Keenan et al., Biochemical Journal, 165, 405 (1977)]. It is also known that dolichol is widely distributed in mammals, and performs a very important function in maintaining the lives of organisms. For example, J. B. Harford et al. showed by in vitro tests using the calf or pig brain white matter that exogenous dolichol enhances incorporation of carbohydrates such as mannose into lipid, and consequently increases the formation of glycoproteins which are important for maintaining the lives of organisms [Biochemical and Biophysical Research Communications, 76,1036 (1977)]. Since the effect of dolichol to incorporate carbohydrates into lipid is remarkable in mature animals as compared with those in the actively growing stage, the action of dolichol has attracted attention for its possible prevention of aging.
R. W. Keenan et al. state that it is important for organisms which rapidly keep growing, for example, those in the infant stage, to take dolichols extraneously so as to supplement the dolichol produced by biosynthesis within their own body [Archives of Biochemistry and Biophysics, 179, 634 (1977)].
Akamatsu et al. determined the quantity of dolichol phosphate in the regenerated liver of a rat and found that the quantity determined is much smaller than that in normal liver and the function of the liver tissues to synthesize glycopropteins is drastically reduced and that the addition of exogenous dolichol phosphate improves the reduced function of glycoprotein synthesis (reported at the 1981 Conference of the Japanese Society of Biochemistry).
In this way, dolichol is a very important substance for organisms, and it is strongly desired to develop its use as a medicine or an intermediate for the production of medicines, cosmetics, etc.
However, it is not easy to isolate dolichol from mammalian tissues. For example, only about 0.6 g at most of dolichol can be obtained from 10 kg of pig liver through complicated separating procedures [See J. Burgos et al., Biochemical Journal, 88, 470 (1963)].
On the other hand, it is extremely difficult by the present day techniques of organic synthesis to produce dolichol by a wholly synthetic process, as can be seen in the light of the complex and unique molecular structure.
It is so far known that polyprenols of the general formula ##STR5## wherein k=4 to 6, which are called betulaprenols, can be isolated from Betula verrucola. However, the betulaprenols so far known contain up to six cis-isoprene units at most, and in order to synthesize dolichol containing homologs having 14, 15 and 16 cis-isoprene units respectively as major components from these betulaprenols, it is necessary to link at least 8 isoprene units while maintaining them in cis-form. This procedure is almost impossible by the present-day organic synthetic techniques.
K. Hannus et al. reported that a polyisoprenyl fraction in an amount of about 1% dry weight was isolated from the needles of Pinus sylvestris, and the fraction consisted of polyisoprenyl acetates with 10 to 19 isoprene units predominantly in the cis-configuration [Phytochemistry, 13, 2563 (1974)]. However, their report does not explain the details of the trans and cis configurations in said polyprenyl acetates. Furthermore, according to a report of D. F. Zinkel et al., a C.sub.90 polyprenol containing 18 isoprene units or a homologous series of polyprenols averaging 18 isoprene units is present in Pinus strobus needle extracts [cf. Phytochemistryl, 11, 3387 (1972)]. However, this report does not contain any detailed analysis of the trans and cis configurations in said polyprenol.
Part of the present inventors, together with their colleagues, previously found that extraction of the leaves of Ginkgo biloba and Cedrus deodara followed by an adequate separation procedure, such as chromatography or fractional dissolution, if necessary following hydrolysis, gives a polyprenyl fraction composed of a mixture of polyprenols and/or acetates thereof which contain 14-22 isoprene units in quite the same trans/cis configurations as in mammalian dolichols and that said polyprenyl fraction is very similar in the distribution of polyprenyl homologs to mammalian dolichols, the only difference being the absence in said fraction of the alpha-terminal saturated isoprene unit and that said polyprenyl fraction, if desired, can be separated relatively easily into the individual constituent polyprenyl homologs (each being homogeneous with respect to the number of isoprene units), and proposed a method of producing dolichols or precursors thereof which comprises reacting such polyprenyl compound or fraction or a reactive derivative thereof with a Grignard reagent or lithium compound derived from a 4-hydroxy-2-methylbutyl halide or a functional precursor thereof (EP No. 0 054 753 Al published on June 30, 1982; U.S. patent application Ser. No. 371,487 which is a continuation-in-part of U.S. patent application Ser. No. 324,636 filed on Nov. 24, 1981, now abandoned). However, this method is disadvantageous in that a 4-hydroxy-2-methylbutyl halide or a functional precursor thereof, which is expensive, is required; the method should desirably be improved.